title: A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations.
abstract: Oligophrenin-1 (OPHN1) is one of at least seven genes located on chromosome X that take part in Rho GTPase-dependent signaling pathways involved in X-linked intellectual disability (XLID). Mutations in OPHN1 were primarily described as an exclusive cause of non-syndromic XLID, but the re-evaluation of the affected individuals using brain imaging displayed fronto-temporal atrophy and cerebellar hypoplasia as neuroanatomical marks. In this study, we describe clinical, genetic and neuroimaging data of a three generation Brazilian XLID family co-segregating a novel intragenic deletion in OPHN1. This deletion results in an in-frame loss of exon 7 at transcription level (c.781_891del; r.487_597del), which is predicted to abolish 37 amino acids from the highly conserved N-terminal BAR domain of OPHN1. cDNA expression analysis demonstrated that the mutant OPHN1 transcript is stable and no abnormal splicing was observed. Features shared by the affected males of this family include neonatal hypotonia, strabismus, prominent root of the nose, deep set eyes, hyperactivity and instability/intolerance to frustration. Cranial MRI scans showed large lateral ventricles, vermis hypoplasia and cystic dilatation of the cisterna magna in all affected males. Interestingly, hippocampal alterations that have not been reported in patients with loss-of-function OPHN1 mutations were found in three affected individuals, suggesting an important function for the BAR domain in the hippocampus. This is the first description of an in-frame deletion within the BAR domain of OPHN1 and could provide new insights into the role of this domain in relation to brain and cognitive development or function.
authors.affiliation: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cíntia Barros
authors.initials: CB
authors.lastname: Santos-Rebouças
authors.affiliation: 1] Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium [2] Human Genome Laboratory, Center for Human, Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belet
authors.affiliation: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Guedes de Almeida
authors.affiliation: Clinical Genetics Service, IPPMG, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Márcia Gonçalves
authors.initials: MG
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Biotechnology, Center for Biosciences and Biotechnology, State University of North Fluminense Darcy Ribeiro, Rio de Janeiro, Brazil.
authors.forename: Enrique
authors.initials: E
authors.lastname: Medina-Acosta
authors.affiliation: Department of Neurology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Paulo Roberto Valle
authors.initials: PR
authors.lastname: Bahia
authors.affiliation: Laboratory of Biotechnology, Center for Biosciences and Biotechnology, State University of North Fluminense Darcy Ribeiro, Rio de Janeiro, Brazil.
authors.forename: Antônio Francisco
authors.initials: AF
authors.lastname: Alves da Silva
authors.affiliation: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Flávia
authors.initials: F
authors.lastname: Lima dos Santos
authors.affiliation: 1] Epilepsy Outpatient Section, Fluminense Federal University, Rio de Janeiro, Brazil [2] Neurology and Neurophysiology Service, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Glenda Corrêa
authors.initials: GC
authors.lastname: Borges de Lacerda
authors.affiliation: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Márcia Mattos Gonçalves
authors.initials: MM
authors.lastname: Pimentel
authors.affiliation: 1] Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium [2] Human Genome Laboratory, Center for Human, Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism; D002648:Child; D055028:Comparative Genomic Hybridization; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D016364:Reading Frames; D017384:Sequence Deletion; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C111952:OPHN1 protein, human